Initiation of substitution therapy and choice of preparation

Testosterone substitution is started when the diagnosis is established and serum testosterone levels below the normal range are found, taking into account the various influences on serum testosterone levels including diurnal variations. In order to establish a diagnosis by documenting low serum testosterone levels, usually determination of testosterone in a serum sample taken between 08.00 and 10.00 in the morning is sufficient (Vermeulen and Verdonck 1992). Pooled sera will not improve diagnostic accuracy (see Chapter 21).

The symptoms of androgen deficiency can be prevented or reversed by testosterone treatment. It is important that a preparation with natural testosterone is selected for treatment so that all functions of testosterone and its active metabolites DHT and estradiol can be exerted (Fig. 13.1). Of all testosterone preparations and routes of application described in Chapter 14, intramuscular injection or oral ingestion of testosterone esters were formerly the most widely accepted and practiced modalities for the treatment of all forms of hypogonadism. Over the last decade, transdermal testosterone preparations have become a valuable alternative, first transdermal patches and, more recently, transdermal gels. The transdermal preparations have the advantage that they can mimic the normal physiologic diurnal rhythm and thus represent the most physiologic form of substitution.

Fig. 13.1 Target organs of testosterone and its active metabolites DHT and estradiol indicating that testosterone needs to be converted to these metabolites to develop the full spectrum of its activity.

For full intramuscular substitution pharmacokinetic and clinical studies show that 200 to 250 mg testosterone enanthate or testosterone cypionate must be injected every two weeks (Cunningham et al. 1990; Davidson et al. 1979; Gooren 1987; Nieschlag et al. 1976; Schulte-Beerbuhl and Nieschlag 1980; Snyder and Lawrence 1980;Sokol etal. 1982). More recently, 1000 mg testosterone undecanoate dissolved in castor oil and injected at 12-week intervals have been shown to be effective in substitution therapy (von Eckardstein and Nieschlag 2002). The long injection intervals and smooth serum levels in the normal range are appreciated by the patients and predict good acceptability of this preparation, once it has become licensed.

If oral substitution is preferred, 40 mg testosterone undecanoate capsules must be given two to four times daily. These doses have been shown to be effective in the majority of hypogonadal men in either open (Franchi etal. 1978; Franchimont etal. 1978; Gooren 1987; Maisey etal. 1981; Morales etal. 1997) or double-blind controlled studies (Luisi and Franchi 1980; Skakkebaek et al. 1981) when libido and potency as well as physical and mental activity were taken as parameters. Although relatively high testosterone doses are consumed with this regimen, liver function is not negatively affected,ascould be shownin35men taking 80 to 200 mg testosterone undecanoate over ten years (Gooren 1994). The patients need to be instructed to ingest the capsules together with a meal in order to guarantee adequate absorption from the gut (Bagchus etal. 2003).

Transdermal testosterone preparations maybe used as a first choice and are specifically suited for patients suffering from fluctuating symptoms caused by testosterone enanthate injections. Another advantage is the self-applicability of these preparations. First a transscrotal patch was developed, consisting of a film containing 10 or 15 mg natural testosterone. These patches are applied daily and lead to physiologic serum testosterone levels (Ahmed et al. 1988; Atkinson et al. 1998; Bals-Pratsch et al. 1988; Carey et al. 1988; Cunningham et al. 1989; Findlay et al. 1989). In our own experience of over ten years adequate long-term substitution can be achieved without serious side-effects under regular use. Serum testosterone levels are maintained in the lower normal range which is sufficient to induce e.g. normal bone density (Behre et al. 1999). Transdermal delivery systems on non-scrotal skin also result in physiological serum levels, depending on the number of patches used (Brocks et al. 1996). Regardless of application to different body areas e.g. back, abdomen, thigh or upper arm, rather similar pharmacokinetic patterns of serum testosterone are achieved (Meikle 1998). Due to the enhancers used in the patches to facilitate absorption, skin irritation occurs in a high percentage of patients, often leading to termination of this mode of testosterone application (Arver et al. 1997; Jordan 1997).

The latest development in androgen replacement therapy is an open testosterone delivery system using a hydroalcoholic gel which was first licensed in the United States and is now also available in Europe for the treatment of hypogonadal men. When applied to the skin, the gel dries rapidly and the steroid is absorbed into the stratum corneum, which serves as a reservoir. Pharmacokinetic studies of this gel (50 or 100 mg) applied to hypogonadal men indicate that testosterone levels increase into the normal range within 30 min, with steady-state levels achieved by 24 h. Studies over six months showed good clinical effects and tolerability, long-term trials are underway.

The choice of testosterone preparation and route of administration is finally up to the patient who over time may gather experience with several preparations and develop his own preference. Younger patients will be more inclined to choose long-acting preparations while the older patient (>50 years) should be advised to use a short-acting preparation (Nieschlag 1998). If therapy has to be stopped due to developing contraindications (e.g. prostate disease), serum testosterone levels will immediately decline to endogenous levels.

If a patient has pronounced androgen deficiency, has never received testosterone and has passed the age of puberty he is immediately treated with a full maintenance dose of testosterone. In cases of secondary hypogonadism when fertility is requested, testosterone therapy can be interrupted and GnRH or hCG/hMG therapy can be implemented until sperm counts increase and a pregnancy has been induced. Testosterone therapy does not prevent the chance of initiating or reinitiating spermatogenesis with releasing or gonadotropic hormones. Once spermatogen-esis has been induced it can be maintained for some time with hCG alone, keeping intratesticular testosterone concentrations high (Depenbusch et al. 2002); this is not the case with testosterone alone at clinically used doses (see also Chapter 5).

Patients with residual testosterone production may not require a full maintenance dose, e.g. Klinefelter patients in an early phase of testosterone deficiency. In these cases injection intervals of testosterone esters may be extended beyond the two-week period; these cases may also be suited for low-dose testosterone undecanoate therapy (i.e. 40 mg once or twice daily) or intermittent transdermal treatment. This dose does not entirely suppress the residual endogenous testosterone production and supplements the lacking hormone.

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